AIMP1
protein-codingaminoacyl tRNA synthetase complex interacting multifunctional protein 1, the group of Aminoacyl tRNA synthetase complex interacting multifunctional proteins
Gene summary
The protein encoded by this gene is a cytokine that is specifically induced by apoptosis, and it is involved in the control of angiogenesis, inflammation, and wound healing. The release of this cytokine renders the tumor-associated vasculature sensitive to tumor necrosis factor. The precursor protein is identical to the p43 subunit, which is associated with the multi-tRNA synthetase complex, and it modulates aminoacylation activity of tRNA synthetase in normal cells. This protein is also involved in the stimulation of inflammatory responses after proteolytic cleavage in tumor cells. Multiple transcript variants encoding different isoforms have been found for this gene. A pseudogene has been identified on chromosome 20. [provided by RefSeq, Dec 2008]
- SCYE1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009843
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009843
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0019502
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009843
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009843
Submitter: ClinGen
AIMP1 was first reported in relation to autosomal recessive hypomyelinating leukodystrophy 3 (HLD3) (OMIM:603605) in 2010 (Feinstein et al., PMID: 21092922). AIMP1 protein function is important in joining tRNAs to their cognate amino acids and in interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes (Khan et al., PMID:30828585). This disease is clinically characterized by developmental delay, microcephaly, and white matter abnormality on MRI and additional variable findings including epilepsy, hypotonia, spasticity, and cerebral atrophy (Hori et al. 2021, PMID: 33402283). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern. The mechanism of pathogenicity is loss of function. Seven variants (3 frameshift, 2 nonsense, 1 missense, 1 splice-site) that have been reported in 18 probands in 7 publications (PMIDs: 21092922, 24958424, 30486714, 30477741, 31618474, 36368352, 36652953) are included in this curation. Of note, one variant (c.115C > T; p.Gln39*) was observed in five probands of Filipino descent and is likely a founder variant in this population. At least two families (seven total affected individuals) with homozygous missense variants in AIMP1 were found to have an isolated neurodevelopmental phenotype (intellectual disability) without hypomyelination or neurodegeneration (PMID: 26173967). Therefore, these probands were not included in this curation, and more evidence is needed to determine if these individuals are representative of a separate disease entity or a wider phenotype spectrum of HLD3. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by an animal model (Zhu et al., PMID: 19717447). Zhu et al. showed that a mouse model lacking the MSC p43 protein exhibited axon degeneration in motor neurons, defective neuromuscular junctions, muscular atrophy, and motor dysfunction (PMID: 19717447). In summary, there is definitive evidence supporting the relationship between AIMP1 and hypomyelinating leukodystrophy 3 (MONDO:0009843), also known as AIMP1-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy GCEP on the meeting date December 18, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009843
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009843
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AIMP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001142416.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 15 | 15 | ||||
| missense | 1 | 78 | 9 | 1 | 89 | |
| nonsense | 5 | 1 | 6 | |||
| start loss | 0 | |||||
| frameshift | 6 | 8 | 14 | |||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 12 | 11 | 79 | 24 | 1 | 127 |
Highest pathogenic variant AF is 0.000045875426
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001135888.2 | 6 | MANE Select | |
| Ensembl | ENSP00000500620.1 | 6 | MANE Select | |
| RefSeq | NP_001135887.1 | 6 | Standard | |
| RefSeq | NP_004748.2 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- tRNA Aminoacylation
- Translation
- Metabolism of proteins
- Metabolism of amino acids and derivatives
- Metabolism
Biological Process
- angiogenesis
- negative regulation of endothelial cell proliferation
- tRNA aminoacylation for protein translation
- apoptotic process
- chemotaxis
Molecular Function
- tRNA binding
- cytokine activity
- protein binding
- protein homodimerization activity
- GTPase binding
Cellular Component
- extracellular space
- nucleus
- endoplasmic reticulum
- Golgi apparatus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394701
- Coding exons
- 7
- Length
- 33683
- Individuals with no LoFs
- 125708
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 37
- Defined
- 125745
- p
- 0.000147
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.207 | 182 | 174 | 1.04 | 0.00000855 | 2198 |
| Missense (PolyPhen) | 45 | 61.779 | 0.7284 | 852 | ||
| Synonymous | 0.500 | 55 | 59.9 | 0.918 | 0.00000311 | 645 |
| Loss of Function | 0.923 | 12 | 16.0 | 0.751 | 8.07e-7 | 200 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-catalytic component of the multisynthase complex. Stimulates the catalytic activity of cytoplasmic arginyl-tRNA synthase (PubMed:10358004). Binds tRNA. Possesses inflammatory cytokine activity (PubMed:11306575). Negatively regulates TGF-beta signaling through stabilization of SMURF2 by binding to SMURF2 and inhibiting its SMAD7-mediated degradation (By similarity). Involved in glucose homeostasis through induction of glucagon secretion at low glucose levels (By similarity). Promotes dermal fibroblast proliferation and wound repair (PubMed:16472771). Regulates KDELR1-mediated retention of HSP90B1/gp96 in the endoplasmic reticulum (By similarity). Plays a role in angiogenesis by inducing endothelial cell migration at low concentrations and endothelian cell apoptosis at high concentrations (PubMed:12237313). Induces maturation of dendritic cells and monocyte cell adhesion (PubMed:11818442). Modulates endothelial cell responses by degrading HIF-1A through interaction with PSMA7 (PubMed:19362550). {ECO:0000250|UniProtKB:P31230, ECO:0000269|PubMed:10358004, ECO:0000269|PubMed:11157763, ECO:0000269|PubMed:11306575, ECO:0000269|PubMed:11818442, ECO:0000269|PubMed:12237313, ECO:0000269|PubMed:19362550}.;
- Disease
- DISEASE: Leukodystrophy, hypomyelinating, 3 (HLD3) [MIM:260600]: A severe autosomal recessive hypomyelinating leukodystrophy characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system. {ECO:0000269|PubMed:21092922}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.159
Intolerance Scores
- LoFtool
- 0.976
- RVIS EVS
- 0.08
- RVIS percentile EVS
- 60.31
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.477
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |